The correspondence between regional distribution of pulmonary ventilation (VA) and perfusion (Q) is central to the efficient function of the lungs in both health and disease. In spite of a vast amount of work devoted to studying the local control of intrapulmonary Q distribution, the equally important control of local VA has been largely overlooked. Preliminary studies using PET have suggested that the distribution of local VA is intimately coupled to that of Q and could be a far more effective and important mechanism than previously appreciated. The primary objective of this project is to study, in an animal model (sheep), the mechanisms by which passive and active factors control the topographic distribution of gas exchange in normal and pathologically non- uniform lungs using positron emission tomography (PET). The aims of our research are: 1) to assess the local contributions of passive mechanisms, such as gravity and structure, and, active controllers, such as bronchial and vascular smooth muscle in determining the local distributions of VA, Q, and VA /Q in normal lungs. 2) To characterize the time dependence and length scale at which these mechanisms operate. And 3) to elucidate the mechanisms by which local control of VA and Q optimize gas exchange in the lung and specifically, the role of the systemic and bronchial circulation pH. Novel PET imaging methods will be used to measure non-invasively the relevant variables of local gas exchange and modern techniques of image processing will be applied to characterize the spatial heterogeneity of the derived functional images. The unique features of our PET imaging method to assess simultaneously Q and VA and the mass transport phenomena in distal airspaces adjacent to the blood gas interface will give insights into basic physiological phenomena that until now have remained elusive. Aside from the valuable physiological information to be derived from this project, the results will have direct clinical applications such as in the management of hypoxemia during pulmonary embolism high altitude pulmonary edema. Finally, this project will yield experimental and analytical tools that will be crucial for understanding, developing and testing of novel methods to optimize gas exchange such as inhaled NO and liquid ventilation.